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Treatment Approaches in Non-Driver Adenocarcinoma

Panelists:Benjamin P. Levy, MD, Mount Sinai Health Systems;Chandra P. Belani, MD, Penn State Cancer Institute;Marina Garassino, MD, National Cancer Institute Milan, Italy;Sarah B. Goldberg, MD, MPH, Yale Cancer Center;Ramaswamy Govindan, MD, Washington University School of Medicine;Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center
Published: Thursday, Sep 08, 2016


Transcript:

Benjamin P. Levy, MD:
Let’s actually move on to a very common scenario in all of our practices, which is when we have a patient that does not have an identifiable mutation. Certainly, we are using chemotherapy. I think we need to remember that chemotherapy works for these patients. It improves survival and, in some studies, improves quality of life. And even for our patients that have identifiable mutations, we use chemotherapy for these patients and it works. I think the chemotherapy story for the adenocarcinoma population, there’s some competing strategies. And I imagine each of us may have a different treatment approach for our stage IV adenocarcinoma patients. So, Chandra, I’m going to start with you. Can you walk us through your treatment approach for a patient that does not have identifiable driver, your chemotherapy selection, whether or not you’re using an anti-angiogenic strategy, and then maintenance as well? What has been your approach? You’ve done a lot of work in this space.

Chandra P. Belani, MD: ECOG established that carboplatin/paclitaxel/bevacizumab was superior to carboplatin/ paclitaxel with a 2-month overall improvement in progression-free survival, and also a 2-month improvement in overall survival. That has been our gold standard. And we have built up on that based on the maintenance studies that were done where Alimta proved to be beneficial in terms of both progression-free survival and overall survival. After induction therapy, we have adopted the use of pemetrexed in the maintenance setting.

Though I think that there is no optimal maintenance treatment, and that’s where ECOG 5508 comes in, which I am the co-chair of. And the three maintenance regimens there, to which patients have been randomized after four cycles of carboplatin/paclitaxel/bevacizumab, are bevacizumab alone, which was used in ECOG 4599, pemetrexed alone or the combination of pemetrexed and bevacizumab. So, actually, not to put in a plug, the study has completed accrual, at this point in time and is awaiting analysis. We will have a definite maintenance therapy in that setting.

Now, I think, on the other hand, the combination of either cisplatin/pemetrexed or carboplatin/pemetrexed is also the regimen of choice in Europe and also in the US. Though we use more carboplatin as compared to what you do in Europe, I think that carboplatin/pemetrexed, with or without bevacizumab, is used in the community setting and also at the academic institutions. And it has shown equivalent effects as compared to the combination of carboplatin/paclitaxel/bevacizumab. So, that’s the other choice that we have. Outside of a clinical trial, I use pemetrexed as a maintenance treatment and on the clinical trial, while we had ECOG 5508, which will answer the question of the definite maintenance treatment.

Benjamin P. Levy, MD: Your induction regimen is generally carboplatin/pemetrexed or carboplatin/paclitaxel/bevacizumab? What are you generally choosing outside of a clinical trial?

Chandra P. Belani, MD: Outside of a clinical, if I’m going to use bevacizumab, I usually use carboplatin/paclitaxel/bevacizumab. There are some data that show that taxanes and bevacizumab have synergistic effects based on the intratumoral pressures. So, I think I see a benefit there. And the randomized trial, which was published, showed that carboplatin/pemetrexed/bevacizumab was equivalent to carboplatin/paclitaxel/bevacizumab. Though there was a second part to it, which we haven’t really answered because in the bevacizumab/pemetrexed arm, the maintenance treatment was the combination of pemetrexed/bevacizumab. Until we establish that, we don’t use two drugs outside of clinical trial in the maintenance setting.

Benjamin P. Levy, MD: And is there a bevacizumab-eligible versus -ineligible patient, and what is that discriminating point for you in terms of clinical characteristics or age?

Chandra P. Belani, MD: We also published the data on the elderly patients from ECOG 4599 trial, where we showed that patients who were greater than 70 years of age really did not benefit from bevacizumab. I think that group probably is an optimal group for treatment with the combination of carboplatin and pemetrexed or cisplatin and pemetrexed without bevacizumab. And, then, patients who have coronary artery disease, or cerebral vascular hemorrhage, or arterial thromboembolism are the groups of patients who should be excluded from bevacizumab. Though I think renal thromboembolism is a relative contraindication. And, we can, if we treat the renal thromboembolism, give bevacizumab to those patients.

Benjamin P. Levy, MD: So, there are competing standards. I’d love to hear from other panelists what their approach is for first-line adenocarcinoma patient. Govindan, how do you approach your garden-variety patient without an actionable mutation?

Ramaswamy Govindan, MD: In the frontline, I tend to use more pemetrexed/carboplatin. I am less persuaded that adding bevacizumab makes a big difference. There have been other studies not showing as much benefit as we have seen with the ECOG study. I do give maintenance pemetrexed for those patients. The ECOG study that Chandra talked about is a very important one. But, definitely, I think in the fit ideal patient with no absolute contraindication, paclitaxel/carboplatin/bevacizumab is an option, that it’s not something that they’re going to ignore.

Benjamin P. Levy, MD: Sarah?

Sarah B. Goldberg, MD, MPH: I agree with what’s been said. I tend to use carboplatin and pemetrexed. I think the trial we were discussing where you compare the two regimens, paclitaxel or pemetrexed, the survival looks similar. There’s differences in toxicity, but, overall, you could say the toxicity looks similar in terms of number of toxic events. I think, just from experience, pemetrexed tends to be easier on patients. There’s no hair loss, which is a big issue for some patients. So, I tend to use pemetrexed thinking it’s similar in terms of clinical outcomes and more tolerable.

Benjamin P. Levy, MD: Mark, your perspective on this?

Mark G. Kris, MD: My go-to thing would be cisplatin/pemetrexed/bevacizumab. For patients that can’t take cisplatin, I’d give paclitaxel/pemetrexed/bevacizumab.

Benjamin P. Levy, MD: So, a non-platinum-based regimen.

Mark G. Kris, MD: A non-platinum-based regimen; three active drugs I try give in. And the nice thing about bevacizumab is that for the vast majority of patients, it can be added to the two other drugs. That’s pretty unusual actually. You can do that without a lot of side effects. I, for better or worse, give both pemetrexed and bevacizumab for maintenance.

Benjamin P. Levy, MD: European perspective, first-line?

Marina Garassino, MD: In Italy, we decided that for patients that are eligible for cisplatin or carboplatin, generally we use pemetrexed. Or, we do carboplatin/pemetrexed and pemetrexed maintenance, or cisplatin/pemetrexed and pemetrexed maintenance. I don’t know why in Europe we don’t use so much carboplatin/Taxol/bevacizumab. Because some people, maybe, are scared about the toxicity, which is manageable at the end. But, in Europe, it’s not the favorite regimen.

Benjamin P. Levy, MD: And, you don’t use bevacizumab with a pemetrexed-containing regimen?

Marina Garassino, MD: No, it’s not reimbursed and it’s impossible.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
Let’s actually move on to a very common scenario in all of our practices, which is when we have a patient that does not have an identifiable mutation. Certainly, we are using chemotherapy. I think we need to remember that chemotherapy works for these patients. It improves survival and, in some studies, improves quality of life. And even for our patients that have identifiable mutations, we use chemotherapy for these patients and it works. I think the chemotherapy story for the adenocarcinoma population, there’s some competing strategies. And I imagine each of us may have a different treatment approach for our stage IV adenocarcinoma patients. So, Chandra, I’m going to start with you. Can you walk us through your treatment approach for a patient that does not have identifiable driver, your chemotherapy selection, whether or not you’re using an anti-angiogenic strategy, and then maintenance as well? What has been your approach? You’ve done a lot of work in this space.

Chandra P. Belani, MD: ECOG established that carboplatin/paclitaxel/bevacizumab was superior to carboplatin/ paclitaxel with a 2-month overall improvement in progression-free survival, and also a 2-month improvement in overall survival. That has been our gold standard. And we have built up on that based on the maintenance studies that were done where Alimta proved to be beneficial in terms of both progression-free survival and overall survival. After induction therapy, we have adopted the use of pemetrexed in the maintenance setting.

Though I think that there is no optimal maintenance treatment, and that’s where ECOG 5508 comes in, which I am the co-chair of. And the three maintenance regimens there, to which patients have been randomized after four cycles of carboplatin/paclitaxel/bevacizumab, are bevacizumab alone, which was used in ECOG 4599, pemetrexed alone or the combination of pemetrexed and bevacizumab. So, actually, not to put in a plug, the study has completed accrual, at this point in time and is awaiting analysis. We will have a definite maintenance therapy in that setting.

Now, I think, on the other hand, the combination of either cisplatin/pemetrexed or carboplatin/pemetrexed is also the regimen of choice in Europe and also in the US. Though we use more carboplatin as compared to what you do in Europe, I think that carboplatin/pemetrexed, with or without bevacizumab, is used in the community setting and also at the academic institutions. And it has shown equivalent effects as compared to the combination of carboplatin/paclitaxel/bevacizumab. So, that’s the other choice that we have. Outside of a clinical trial, I use pemetrexed as a maintenance treatment and on the clinical trial, while we had ECOG 5508, which will answer the question of the definite maintenance treatment.

Benjamin P. Levy, MD: Your induction regimen is generally carboplatin/pemetrexed or carboplatin/paclitaxel/bevacizumab? What are you generally choosing outside of a clinical trial?

Chandra P. Belani, MD: Outside of a clinical, if I’m going to use bevacizumab, I usually use carboplatin/paclitaxel/bevacizumab. There are some data that show that taxanes and bevacizumab have synergistic effects based on the intratumoral pressures. So, I think I see a benefit there. And the randomized trial, which was published, showed that carboplatin/pemetrexed/bevacizumab was equivalent to carboplatin/paclitaxel/bevacizumab. Though there was a second part to it, which we haven’t really answered because in the bevacizumab/pemetrexed arm, the maintenance treatment was the combination of pemetrexed/bevacizumab. Until we establish that, we don’t use two drugs outside of clinical trial in the maintenance setting.

Benjamin P. Levy, MD: And is there a bevacizumab-eligible versus -ineligible patient, and what is that discriminating point for you in terms of clinical characteristics or age?

Chandra P. Belani, MD: We also published the data on the elderly patients from ECOG 4599 trial, where we showed that patients who were greater than 70 years of age really did not benefit from bevacizumab. I think that group probably is an optimal group for treatment with the combination of carboplatin and pemetrexed or cisplatin and pemetrexed without bevacizumab. And, then, patients who have coronary artery disease, or cerebral vascular hemorrhage, or arterial thromboembolism are the groups of patients who should be excluded from bevacizumab. Though I think renal thromboembolism is a relative contraindication. And, we can, if we treat the renal thromboembolism, give bevacizumab to those patients.

Benjamin P. Levy, MD: So, there are competing standards. I’d love to hear from other panelists what their approach is for first-line adenocarcinoma patient. Govindan, how do you approach your garden-variety patient without an actionable mutation?

Ramaswamy Govindan, MD: In the frontline, I tend to use more pemetrexed/carboplatin. I am less persuaded that adding bevacizumab makes a big difference. There have been other studies not showing as much benefit as we have seen with the ECOG study. I do give maintenance pemetrexed for those patients. The ECOG study that Chandra talked about is a very important one. But, definitely, I think in the fit ideal patient with no absolute contraindication, paclitaxel/carboplatin/bevacizumab is an option, that it’s not something that they’re going to ignore.

Benjamin P. Levy, MD: Sarah?

Sarah B. Goldberg, MD, MPH: I agree with what’s been said. I tend to use carboplatin and pemetrexed. I think the trial we were discussing where you compare the two regimens, paclitaxel or pemetrexed, the survival looks similar. There’s differences in toxicity, but, overall, you could say the toxicity looks similar in terms of number of toxic events. I think, just from experience, pemetrexed tends to be easier on patients. There’s no hair loss, which is a big issue for some patients. So, I tend to use pemetrexed thinking it’s similar in terms of clinical outcomes and more tolerable.

Benjamin P. Levy, MD: Mark, your perspective on this?

Mark G. Kris, MD: My go-to thing would be cisplatin/pemetrexed/bevacizumab. For patients that can’t take cisplatin, I’d give paclitaxel/pemetrexed/bevacizumab.

Benjamin P. Levy, MD: So, a non-platinum-based regimen.

Mark G. Kris, MD: A non-platinum-based regimen; three active drugs I try give in. And the nice thing about bevacizumab is that for the vast majority of patients, it can be added to the two other drugs. That’s pretty unusual actually. You can do that without a lot of side effects. I, for better or worse, give both pemetrexed and bevacizumab for maintenance.

Benjamin P. Levy, MD: European perspective, first-line?

Marina Garassino, MD: In Italy, we decided that for patients that are eligible for cisplatin or carboplatin, generally we use pemetrexed. Or, we do carboplatin/pemetrexed and pemetrexed maintenance, or cisplatin/pemetrexed and pemetrexed maintenance. I don’t know why in Europe we don’t use so much carboplatin/Taxol/bevacizumab. Because some people, maybe, are scared about the toxicity, which is manageable at the end. But, in Europe, it’s not the favorite regimen.

Benjamin P. Levy, MD: And, you don’t use bevacizumab with a pemetrexed-containing regimen?

Marina Garassino, MD: No, it’s not reimbursed and it’s impossible.

Transcript Edited for Clarity
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